Project Summary/Abstract A large percentage of the aging population experiences cognitive decline, which includes impairments in learning, memory, processing speed, and executive function. Although there has been intensive research into the etiology of cognitive decline with age, the specific mechanisms responsible for cognitive impairment remain elusive. This lack of knowledge severely limits the development of effective therapeutic interventions. Neurosteroids are steroids that have the ability to alter neuronal excitability through interaction with ligand-gated channels or other cell surface receptors. They also have the ability to affect gene expression through classical steroid hormone receptors. Many neurosteroids are synthesized from progesterone (PRG) through a network of steroidogenic enzymes known to be expressed in both neurons and glial cells and include, but are not limited to, glucocorticoids (CORT), estrogens (E), testosterone (T) and allopregnanolone. Previous research indicates that allopregnanolone decreases in several models of neurodegenerative disease where deficits in cognitive function are evident. Administration of allopregnanolone improves cognitive function in mouse models of Alzheimer?s disease (AD) and Niemann-Pick C disease (NPC). Nevertheless, few studies have assessed whether brain levels of allopregnanolone levels decrease with age, and to our knowledge, no studies have assessed its contribution to age-related cognitive decline. LC/MS analysis presented in this application reveal that allopregnanolone declines significantly in brain tissue of male and female mice. Our preliminary data indicate that a single injection of allopregnanolone significantly increases neurogenesis and improves learning and memory in aged mice. Importantly, inflammatory cytokines have been shown to regulate PRG metabolizing enzymes in the periphery but their role in regulating allopregnanolone in the brain remain unknown. The hypothesis of this application is that the age-related increase in inflammatory cytokines alters activity of PRG metabolizing enzymes resulting in a decline in allopregnanolone, reduced neurogenesis and cognitive impairment in aged mice. Three aims are proposed: 1) Determine the specific intra-cellular mechanisms governing the age-related decline in allopregnanolone and consequences of replacement, 2) Investigate whether allopregnanolone increases neural stem cell (NSC) proliferation and/or NSC survival, and if this increase is mediated through increases in paracrine IGF-1 levels.